Research Archive Citation for published version: Ornella Corazza, Franceso Saverio Bersani, Roberto Brunoro, Giuseppe Valeriani, Giovanni Martinotti, and Frabrizio Schifano, ‘The diffusion of Performance and Image-Enhancing Drugs (PIEDs) on the Internet: The Abuse of the Cognitive Enhancer Piracetam’, Substance Use & Misuse, Vol. 49 (14): 1849-1856, December 2014. DOI: https://doi.org/10.3109/10826084.2014.912232 Document Version: This is the Accepted Manuscript version. The version in the University of Hertfordshire Research Archive may differ from the final published version. Copyright and Reuse: This Manuscript version is distributed under the terms of the Creative Commons Attribution license, https://creativecommons.org/licenses/by/4.0/ , which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited. Enquiries If you believe this document infringes copyright, please contact the Research & Scholarly Communications Team at [email protected] Performance and Image Enhancing Drugs: the abuse of cognitive enhancer Piracetam Ornella Corazza (1), Francesco Saverio Bersani (1, 2), Roberto Brunoro (1), Giuseppe Valeriani (1, 3), Giovanni Martinotti (4), Fabrizio Schifano (1). 1. School of Life and Medical Sciences, University of Hertfordshire, UK 2. Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy 3. Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy 4. Department of Neuroscience and Imaging, Gabriele d’Annunzio University, Chieti, Italy Running Title: Piracetam misuse: a review of online reports Abstract Introduction: Performance and Image Enhancing Drugs (PIED), also known as “lifestyle drugs”, are increasingly sold on the Internet to enhance cognitive as well as sexual, muscular, attentive and other natural capacities. Our analysis focus on the misuse of the cognitive enhancer Piracetam. Methods: A literature review was carried out in PsychInfo and Pubmed database. Considering the absence of peer-reviewed data, additional sources of unstructured information from the Internet was carried out between February 2012 and July 2013. Additional searches were conducted using the Global Public Health Intelligence Network (GIPHIN), a secure Internet-based early warning system developed by Health Canada and the World Health Organization (WHO), which monitors media reports in six languages, Arabic, Chinese, English, French, Russian and Spanish. Results: Piracetam is sold via illicit online pharmacies with no need of prescription at low prices. Buyers, mainly healthy individuals, purchase the product to enhance study and work-related performances as well as for recreational purposes. Its non-medical use is often associated with the occurrence of side effects such as hallucinations, psychomotor agitation, dysphoria, tiredness, dizziness, memory loss, headache and severe diarrhea; moreover, several users declared to not have felt any cognitive improvement nor psychedelic effects. Conclusions: This is a new and fast growing trend of abuse that needs to be extensively monitored and studied also by using near real-time and unstructured sources of information such as Internet news and online reports in order to acquire rapid knowledge and understanding. Products sold online might be counterfeits and this enhances the health risks. Key Words: Piracetam, Performance and Image Enhancing Drugs, Addiction, Drug Abuse, Cognitive Enhancer, Online Pharmacies. 1. INTRODUCTION In recent years, a rapidly spreading of substances known as ‘Performance and Image Enhancing Drugs’ (PIED), also known as ‘lifestyle drugs’, has been recorded (Evans-Brown, McVeigh, Perkins, & Bellis, 2012). PIEDs are mainly sold online, via illicit online pharmacies, as the most immediate way to enhance cognitive, sexual, muscular, attentive and other natural capacities, even if their level of safety, composition and legal status are mostly unknown (European Monitoring Centre for Drugs and Drug Addiction [EMCDDA], 2010; EMCDDA, 2011; Advisory Council on the Misuse of Drugs [ACMD], 2011; Corazza, et al., 2011; Schifano, et al., 2006; Larance, Degenhardt, Copeland, & Dillon, 2008). These also include pharmaceutical products, which can be bought without a prescription and at discounted prices, such as Pregabalin and Adderall (Orizio, et al., 2009; Littlejohn, Baldacchino, Schifano, & Deluca, 2005). In particular, this article will focus on Piracetam, a cognitive enhancer, which has been abused by healthy individuals to enhance their functions in study and work-related performances (Schifano, et al., 2003; Corazza, et al., 2013). Piracetam is a cyclic derivative of the neurotransmitter γ-aminobutyric acid (GABA), originally marketed in 1971 by UCB Pharma. It was the first ‘nootropic’ drug (Giurgea, 1972), an agent that acts on cognitive function without causing sedation or stimulation (Winblad, 2005). It was found originally to be effective as a protective agent in hypoxia-induced amnesia. Although piracetam is a derivative of GABA, its mechanism of action appears to be unrelated to the properties of this neurotransmitter. Piracetam affects a number of neuronal proteins; some evidence suggests that piracetam can act at the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor as an allosteric modulator binding in six different positions (Ahmed & Oswald, 2010) and that it may have an effect on NMDA glutamate receptors (Cohen & Müller, 1993). However, while the exact mode of action of piracetam is a matter of debate, there is increasing evidence that its underlying effect is to restore cell membrane fluidity (Fassoulaki, Kostopanagiotou, Kaniaris, & Varonos, 1985; Peuvot, Schank, Deleers, & Brasseur, 1995). Restored membrane fluidity induced by Piracetam may have a number of physiological consequences including restored neurotransmission (Winblad, 2005), increased oxygen consumption in the brain (Jordaan, Oliver, Dormehl, & Hugo, 1996), enhanced neuroplasticity (Brandao, et al., 1996), neuroprotection (Brandao, Paula-Barbosa, & Cadete-Leite, 1995) and anticonvulsant action (Benesova, 1980). Consistent with its varied pharmacological effects, Piracetam has documented benefit in a diverse range of indications. The largest amount of data is about the therapeutics use of Piracetam to treat early Alzheimer’s disease and age-associated memory impairment (Waegemans, et al., 2002); a large meta-analysis of all available clinical studies provided compelling evidence for the global efficacy of piracetam in a diverse group of older subjects with cognitive impairment (Waegemans, et al., 2002). This proposal was later supported by observations that piracetam specifically enhances membrane fluidity in aged brain material, showing no effect in membranes from young brains (Müller, et al., 1997). In addition to Alzheimer’s disease and age-associated memory impairment, Piracetam showed good clinical outcomes in the treatment of a range of neuropsychiatric disorders including vertigo, cortical myoclonus, dyslexia, neuropathic pain and tardive dyskinesia (Winblad, 2005; Danilova Grafova, & Reshetniak, 1996; Libov, et al., 2007). Piracetam doses usually range between 2.4 g/die and 8 g/die, even if in the treatment of cortical myoclonus it can be administered at higher dosages (up to 24 g/die) (Winblad, 2005). In this context, the present study aims to identify and investigate the non-medical use of Piracetam, while collecting unprecedented information on its psychoactive effects. 2. MATERIALS AND METHODS The literature on Piracetam misuse was searched in PsychInfo and Pubmed databases. Considering the absence of peer-reviewed data on its misuse, results were integrated with a multilingual qualitative assessment of a range of websites, drug fora and other online resources (i.e.: newsgroups, chatrooms, mailing lists, e-newsletters, bulletin boards and videos). Between February 2012 and July 2013, exploratory qualitative searches of 227 websites have been carried out in English using generic and specific keywords, such as “legal highs”, “research chemicals”, “online pharmacy”, “piracetam”, and “nootropil” in the Google search engine. These websites were monitored on a regular basis, daily (n=32), weekly (n=168) or monthly (n=27) depending on relevance. Links from forums, websites and other related material, including newspapers and magazines, were followed as well. Additional searches were carried out in the database provided by the Global Public Health Intelligence Network (GPHIN). This is a secure Internet-based early warning system that gathers preliminary reports of public health significance by monitoring global media sources in near 'real-time', 24 hours a day, 7 days a week basis. GPHIN is operated by the Public Health Agency of Canada, and monitors news sources and websites across the globe in 9 languages (e.g. English, French, Farsi, Portuguese, Arabic, Russian, Spanish, and Chinese simplified/traditional) (Keller, et al., 2009). While a series of algorithms are used and adjusted to capture relevant information, analysis of relevant data since 2003 was also carried out manually by a multidisciplinary and multilingual team of analysts. Permission for the study was granted by the School of Pharmacy Ethics Committee, Hatfield, UK (15 December, 2010; PHAEC/10-42). 3. RESULTS Piracetam is sold online via illicit websites with no need for prescription (see Table 1). Some retailers require an initial ‘online consultation’ with an unknown ‘cyber-doctor’